Pharmaceutical preparation for the treatment of peptic ulcer

ABSTRACT

A pharmaceutical preparation or the treatment of peptic ulcer comprising an active principle, notably a peptide of the following structure: 
     
         Tyr-D-Ala-Gly-Phe-Leu-Arg 
    
     and a pharmaceutically acceptable vehicle.

FIELD OF THE INVENTION

The present invention relates to the art of pharmacology and, morespecifically, to a novel pharmaceutical preparation for the treatment ofpeptic ulcer.

BACKGROUND OF THE INVENTION

It is known in the art that various preparations can be employed ingastroenterology for the treatment of peptic ulcer such asanticholinergic agents--atropine, glycopyrolate, antacids--aluminiumhydroxide, calcium carbonate and the like (cf. Cristensen et al.,Gastroenterology. 1977, v. 73, pp. 1170-1178).

The antiulcerous effect of anticholinergic preparations and antacids isbased on their ability of lowering acidity of the gastric juice,wherefore these preparations are administered in high doses. The use ofsuch doses of the preparations is accompanied by the development ofnumerous side effects.

At present cymethidin is considered to be the most effective preparationfor the treatment of peptic ulcer; its effect is based on blocking H₂-receptors of histamine (cf. Brimblecombe et al., Gastroenterology,1978, v. 74, pp. 339-347). As the same time cymethidin gives a number ofside effects: it causes endocrinous changes; being an antiandrogen, itaffects metabolism of pharmaceutical preparations in liver.

Described in the literature is a peptide having the following structure:Tyr-D-Ala-Gly-Phe-Leu-Arg (Chavkin, Goldstein, Proc. Natl. Acad. Sci.USA. 1981, v. 78, pp. 6543-6547). However, its possible applicationshave not been specified.

DISCLOSURE OF THE INVENTION

The pharmaceutical preparation according to the present invention isnovel and hitherto unknown from the literature.

The present invention is directed to the utilization of a novelpharmaceutical preparation for the treatment of peptic ulcer whichprovides an accelerating effect on processes of ulcer healing, has a lowtoxicity, a broad spectrum of therapeutic action and causes no sideeffects.

This object is accomplished by the use of a pharmaceutical preparationfor the treatment of peptic ulcer comprising an active ingredient and apharmaceutically acceptable vehicle which contains, as the activeingredient, a peptide of the following structure:

    Tyr-D-Ala-Gly-Phe-Leu-Arg.

The preparation according to the present invention can be administeredin diverse pharmaceutical forms (injections, solutions, tablets and thelike). It is preferable to use the preparation according to the presentinvention in the form of injectable solutions with a content of theactive principle of 0.1-0.5% by weight. As the pharmaceuticallyacceptable vehicle the preparation preferably contains bidistilled wateror a 0.9% aqueous solution of sodium chloride.

The preparation according to the present invention in the form oftablets preferably contains the active ingredient in an amount of 10 to50 mg per tablet. As the pharmaceutically acceptable vehicle for tabletsit preferably contains starch, glucose or lactose.

The preparation of this invention provides an accelerating effect onprocesses of healing of peptic ulcer of the duodenum and stomach.Physiological effects of the preparation according to the presentinvention are revealed in acceleration of scarring at the site of ulcer.

The preparation is characterized by a low toxicity, a small single dose,and an effective therapeutic action. The preparation is adapted for thetreatment of peptic ulcer.

BEST MODE OF CARRYING OUT THE INVENTION

The preparation for the treatment of peptic ulcer according to thepresent invention was experimentally tested on animals and clinically onhumans.

The effectiveness of the preparation was studied on an experimentalmodel of a cystamine duodenal ulcer in rats and on a model of gastriculcers in rats caused by immobilization for 24 hours.

Duodenal ulcers were induced by means of a subcutaneous administrationof cystamine hydrochloride in a single dose of 350 mg/kg.

The preparation according to the present invention was alsosubcutaneously administered twice a day in a physiological solution. Inthe experiments 350 male rats of the V-starline of a 150-200 g mass wereused. The animals were slaughtered by decapitation 48 hours afteradministration of cystamine. The state of the mucous membrane of theduodenum was visually assessed by means of a binocular magnifying glass(x5) using the following scale: 0--the mucous membrane is intact,2--single ulcer, 3--plural ulcers, 4--penetrating ulcers. The severityof injury in each group of animals was assessed by an average pointfigure; also calculated was the frequency of injury (the number ofanimals with ulcers/the number of animals in the group). For a totalevaluation an ulcer index was used which was calculated by the formula:

    Index=Severity+Doubled Frequency.

The results obtained for administration of different doses of thepreparation according to the present invention are shown in thefollowing Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect of the preparation according to the present in-                        vention on the development of duodenal ulcers in rats                         Dose of the                                                                            Number                                                               preparation                                                                            of       Characteristics                                             (μg/kg)                                                                             rats     Severity    Frequency                                                                             Index                                   1        2        3           4       5                                       ______________________________________                                        Control  60       1.78 ± 0.17                                                                            0.66    3.10                                     1       20       0.89 ± 0.24*                                                                           0.44    1.70                                     5       20       0.57 ± 0.25*                                                                            0.29*  1.15                                    12       40       0.28 ± 0.14*                                                                            0.13*  0.54                                    50       20       0.67 ± 0.24*                                                                            0.28*  1.23                                    125      20       1.08 ± 0.34                                                                            0.50    2.08                                    300      20       1.70 ± 0.42                                                                            0.70    3.10                                    ______________________________________                                         *Probability <0.05.                                                      

The preparation according to the present invention had an antiulcerousactivity within a broad range of doses of from 5 to 50 μg/kg. Themaximum effective was the dose of 12 μg/kg. A considerable increase ofthe preparation dose caused a reduced antiulcerous effect of thepreparation.

In a separate series of experiments a comparative study of the effect ofthe preparation according to the present invention and cymethidin on theformation and progress of experimental duodenal ulcers. 170 rats wereused. After administration of cystamine over several weeks the firstgroup of animals were injected twice a day with the preparationaccording to the present invention in the maximum effective dose (12μg/kg), the second group--cymethidin--in the dose of 7 mg/kg a day whichcorresponded to a standard dose used for the treatment of peptic ulcerin human beings. The animals of the control group were injected with aphysiological solution. The slaughter of the animals was effected ingroups of 10 animals within different periods after the beginning of theexperiment. The obtained results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Variation of the ulcer index under the effect of the                          preparation of this invention and cymethidin                                  Prepara-                                                                              Time                                                                  tion    24 hrs* 48 hrs  72 hrs                                                                              7 ds**                                                                              14 ds                                                                              21 ds                                                                              28 ds                           ______________________________________                                        Control 3.1     3.3     3.2   1.8   1.2  0.4  0                               Prepara-                                                                              1.4     0.4     0.6   0     0    --   --                              tion of                                                                       this in-                                                                      vention                                                                       Cymethidin                                                                            1.6     1.6     1.5   0.8   0                                         ______________________________________                                         *hrs  hours,                                                                  **ds  days.                                                              

Therefore, a complete healing of ulcers under the effect of thepreparation according to the present invention took place by the end ofthe 1-st week, while under the effect of cymethidin--by the end of thesecond week. After 48 hours the preparation according to the presentinvention caused a considerably greater reduction of the index ascompared to cymethidin. The single dose of the preparation according tothe present invention was by 600 times smaller than that of cymethidin.

Origination of gastric ulcers in rats was caused by immobilization for24 hours in the dorsal position at the temperature of 25° C. Experimentswere carried out with 120 male rats with a mass of 150-200 g. Theanimals were slaughtered by decapitation immediately on completion ofthe immobilization. The preparation according to the present inventionwas administered once subcutaneously 30 minutes after the beginning ofimmobilization. The intensity of erosio-ulcer injuries of the stomachwas evaluated visually and expressed as a total of maximum length of alldefects of the stomach mucous membrane (in mm). The test results areshown in Table 3 hereinbelow.

                  TABLE 3                                                         ______________________________________                                        Effect of the preparation according to the present                            invention on stomach cancer in rats                                                       Dose of the preparation, μg/kg                                 Parameter                                                                             Control   1          12      125                                      ______________________________________                                        Number of                                                                             30        30         30      30                                       animals                                                                       Intensity                                                                             10.8 ± 1.8                                                                           3.2 ± 0.7*                                                                            2.9 ± 0.7*                                                                         4.7 ± 1.2*                            mm                                                                            ______________________________________                                         *Probability <0.05.                                                      

Therefore, the preparation according to the present inventionsubstantially lowers the intensity of erosion-ulcer injuries of thestomach mucous membrane in rats upon immobilization thereof. The maximumactivity of the preparation according to the present invention wasrevealed upon administration thereof in the dose of 12 μg/kg.

Upon slaughter of the animals blood was sampled from cervical vesselsand in its serum the concentration of gastrin was determined. Theresults obtained are shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Effect of the preparation according to the present                            invention on concentration of gastrin in rats' blood serum                    Parame-  Vivarium                                                                            Test  Preparation dose μg/kg                                No.                                                                              ter   control                                                                             control                                                                             1     12    125                                          __________________________________________________________________________    1. Number of                                                                           20    30    30    30    30                                              animals                                                                    2. Gastrin,                                                                            46.8 ± 2.1                                                                       60.9 ± 3.9                                                                       51.8 ± 8.0                                                                       44.0 ± 4.6*                                                                      60.2 ± 10.9                                  pg/ml                                                                      __________________________________________________________________________     *Probability < 0.05.                                                     

As it follows from the above Table 4 the preparation according to thepresent invention when administered in the dose of 12 μg/kg certainlylowers the level of gastrin which has been elevated in rats subjected toimmobilization.

In experiments on 50 male rats the effect of the preparation accordingto the present invention on the production of hydrochloric acid by thestomach was studied. The rats' pylorus was preliminarily ligated,whereafter the preparation of this invention was subcutaneouslyadministered in a single dose. The rats were slaughtered 1 hourafterwards, the amount of gastric juice was measured (in ml), as well asits acidity in titration units. The test results are shown in Table 5hereinbelow.

                  TABLE 5                                                         ______________________________________                                        Effect of the preparation according to the present                            invention on secretion of hydrochloride acid in rats                                         Dose of the preparation,                                                      μg/kg                                                       No.  Parameter Control   1       12    125                                    ______________________________________                                        1.   Juice vol-                                                                              1.97 ± 0.12                                                                          1.94 ± 0.37                                                                        0.87 ±                                                                           1.91 ± 0.47                              ume, ml                     0.07                                         2.   Acidity,  46.8 ± 4.2                                                                           30.2 ± 2.6*                                                                        32.5 ±                                                                           31.9 ± 2.3*                              titr. units                 1.9*                                         ______________________________________                                         *P < 0.05.                                                               

Therefore, the preparation according to the present invention reducedacidity of the gastric juice in all doses without, however, changing thevolume of gastric secretion.

The above experimental studies have shown a clearly pronouncedprotective effect of the preparation according to the present inventionon the mucous membrane of the stomach and duodenum which causes itsantiulcerous effect. This effect of the preparation according to thepresent invention is enhanced by its inhibiting action on secretion ofgastrin and hydrochloric acid.

The study of toxicity of the preparation according to the presentinvention has shown a low toxicity upon a single administration of thepreparation. The dose of the preparation causing death of 50% of whitemice (LD₅₀) was 520 mg/kg (variation from 433 to 624 mg/kg) uponintravenous administration. IN V-star rats the LD₅₀ upon intravenousadministration of the preparation was 270 mg/kg.

The chronical toxicity of the preparation according to the presentinvention was studied for 2 months on rats, rabbits and dogs; thepreparation was administered daily in a single-time injectionintramuscularly in the doses of 0.2 and 2.0 mg/kg to separate groups ofanimals of each species. No generally toxic effect was observed. Nocertain changes on the part of hematological and biochemicalcharacteristics of blood, urina analyses were observed. The data offunctional tests proved lack of changes in the function of lever,kidneys, thyroid gland and pancreas. No certain changes were observed inthe level of sex hormones, adrenal cortex hormones.

The histological studies of liver, lungs, kidneys, heart, hypophysis,sexual glands of the animals administered with the preparation accordingto the present invention in the dose of 2 mg/kg (i.e. by 100 timeshigher than the purported therapeutic dose) have shown that thepreparation causes no substantial morphological changes.

In the investigation of the mutagenous activity of the preparationaccording to the present invention on mice of the C 57 BL/6 line noincrease of chromosomic injuries was revealed in cells of bone marrow ofthe mice which points to the absence of mutagenous activity in thepreparation according to the present invention.

The preparation was tested in clinic on 40 patients suffering fromduodenal peptic ulcer. The control groups consisted of 20 patientstreated with cymethidin in the daily dose of 800 mg. Only male patientswere subjected to the treatment, their age varied from 22 to 56 years.The duration of the disease was different: from newly detected ulcer to28 years of the disease. The diagnosis of the peptic ulcer was made onthe basis of generally accepted clinical tests with an obligatory use ofthe gastroduodenoscopy. The gastroduodenoscopy was carried out prior toadministration of the preparation and 14, 21 and 28 days thereafter (thetwo latter endoscopy were carried out only in the use of non-scarringulcers).

On the first day and 14 days after the administration of the preparationaccording to the present invention blood was taken for biochemicalanalyses, determination of the concentration of a number of hormones. Atthe same time, analyses of urine and stood were performed. During thegastroduodenoscopy biopsy was taken from the fundal and antral sectionsof the stomach, as well as from duodenum cap. At the beginning and atthe end of administration of the preparation according to the presentinvention the secretory function of the stomach was studied with theassessment of the basal and pentagastrin-stimulated secretion ofhydrochloric acid.

The preparation was administered intramuscularly in a dose of 10-15μg/kg in a 0.9% aqueous solution of sodium chloride twice a day (in themoring at 7 a.m. and in the evening at 19 p.m.). The treatment coursewas 14-28 days, the course dose of the preparation was 30-60 mg. Apartfrom the preparation, the patients were given no additionalpharmaceuticals, antacids were also excluded.

An average term of healing of the duodenal ulcer in the group ofpatients treated with the preparation according to the present inventionwas 22.8 days. By the end of the 2-nd week of the treatment the scarringof ulcer was found in 47.5% of the patients; by the end of the 3-rd weekthe ulcer healed in 85% of the patients; by the end of the fourth weekthe ulcer was not scarred only in one patient, i.e. healing took placein 97.5% of the cases.

In the patients treated with cymethidin in the dose of 200 mg 4 times aday by the end of the 3-rd week the healing of ulcer was observed in 65%of the patients which is essentially lesser a percentage than for thesame period of treatment with the preparation according to the presentinvention (85%).

The treatment with the preparation according to the present inventionaccelerated disappearace of pains in the epigastric regioncharacteristic for the peptic ulcer disease: on the 3-rd day painsdisappeared in 50% of the patients, by the end of the 2-nd week of thetreatment no pains were recorded in 97.5% of the patients. In the caseof treatment with cymethidin by the end of the 2-nd week pains werestill noted in 35% of the patients.

No clinically pronounced side phenomena were observed against thebackground of administration of the preparation according to the presentinvention, except for 2 patients who displayed a slight skin irritationwhich stopped after administration of antihistamine preparationswithout, however, canceling the preparation according to the presentinvention.

The administration of the preparation according to the present inventioncaused no essential deviations of the function of the cardio-vascularsystem: electrocardiogram, arterial pressure, heart's beat rate. In 3patients with liability to the arterial hypertension normalization ofthe arterial pressure was observed against the background ofadministration of the preparation of this invention.

Analyses of gastric juice were carried out both before and after 2 weeksof administration of the preparation using the fraction method with theassessment of the basal production of hydrochloric acid and secretion inresponse to stimulation by an intramuscular single-time administrationof pentagastrin in the dose of 5 μg/kg. The test results are shown inTable 6 hereinbelow.

                  TABLE 6                                                         ______________________________________                                        Secretion of hydrochloric acid prior to and after treatment                   with the preparation according to the present invention                       Basal secretion      Stimulated secretion                                             before     after     before after                                             treat-     treat-    treat- treat-                                    Parameter                                                                             ment       ment      ment   ment                                      ______________________________________                                        Juice vol-                                                                            180.2 ± 19.1                                                                          115.3 ±                                                                              212.0 ±                                                                           198.6 ± 30.3                           ume, ml            19.8*     14.1                                             Acid eja-                                                                             21.8 ± 1.4                                                                            10.6 ± 3.4*                                                                           36.6 ±                                                                           36.1 ± 7.8                             culation,                    3.3                                              mequiv/h                                                                      ______________________________________                                         *Probability < 0.05.                                                     

Therefore, the treatment with the preparation according to the presentinvention resulted in a reduction of the basal secretion of hydrochloricacid, providing no effect on the secretory response of the gastricglands to the stimulation by pentagastrin.

The study of hematological characteristics (hemoglobin, leukocytes,eosinophilic, neutrophilic leukocytes, lymphocytes, monocytes,ESR/erythrocyte sedimentation rate/) was effected weekly; the treatmentwith the preparation according to the present invention proved to benon-affecting the studied characteristics.

In the patients treated with the preparation according to the presentinvention once every two weeks the following characteristics weredetermined in blood: glucose, transaminases, amylase, alkaliphosphatase, urea, creatinine, total protein, bilirubin,creatinphosphokinase, lactatedehydrogenase, cholinesterase,leucinaminopeptidase, gamma-glutamyltranspeptidase,glutamatedehydrogenase, potassium, calcium, sodium, chlorine. No certainchanges of these parameters were noted against the background of thetreatment with the preparation according to the present invention. In 3patients there was noted a temporary increase in the activity ofasparagic transaminase in blood which diappeared upon a repeateddetermination of the enzyme a week afterwards. Other characteristicscharacterizing the functional state of the liver were not changed in thepatients.

In 20 patients the basal concentration of a number of hormones wasdetermined in plasma both prior to and after the treatment with thepreparation according to the present invention using radioimmunologicalmethods: gastrin, insulin, glucagon, growth hormone, adrenocorticotropichormone, prolactin, thyrotropic hormone, thyroxin, triiodothyronine,follicle stimulating hormone, luteinizing hormone, aldosterone,hydrocortone, estradiol, progresterone and testosterone. Concentrationsof all hormones in blood were not changed; only an uncertain increase ofthe basal level of insulin was observed (12.1±±0.67 μED/ml prior to thetreatment, 16.7±2.2 μED/ml after the treatment).

Morphological studies were effected on 17 patients treated with thepreparation according to the present invention. Biopsy was taken throughan endoscope from an intact mucous membrane of the duodenum, from theantral and fundal sections of the stomach. The biopsy samples werefixed, sealed in paraffin. Serial sections with a thickness of 3-5 μmwere dyed by hematoxylin-eosine and also by methods ofimmunocytochemical dyeing using specific antiserum towards gastrin I-17(to reveal G-cells), towards somatostatin I-14 (for visualization ofD-cells) and the complex peroxidase-antiperoxidase. The number ofendocrinic cells was counted by means of a special screen on 1 mm² ofthe mucous membrane of the stomach and intestine. The results ofcalculations were compared with the characteristics obtained in animmunocytochemical analysis of biopsy samples taken from 12 persons ofthe control group (substantially healthy people).

The general morphological pattern prior to the treatment revealed anincreased infiltration of the mucous membrane of the stomach andduodenum by lymphocytes and plasmatic cells, as well as a decreasedmitotic index in the epithelium. After the treatment with thepreparation according to the present invention in 53% of the patients anenhanced lympho-plasmacytic infiltration was observed as compared to thecorresponding characteristics prior to the treatment, in 35% of thepatients no changes were revealed, in 12% of the patients thisinfiltration was reduced. At the same time, almost double increase ofthe mitotic index was noticed which could point to more intensiveprocesses of regeneration in the mucous membrane.

The variation of the number of endocrinic cells is shown in thefollowing Table 7.

                  TABLE 7                                                         ______________________________________                                        Effect of the preparation according to the present inven-                     tion on the number of endocrinic cells in the mucous mem-                     brane of the antral section of the stomach and duodenum                                        G-cells,  D-cells,                                           Location         per mm.sup.2                                                                            per mm.sup.2                                       ______________________________________                                        Antral section of the                                                         stomach:                                                                      Control          293 ± 27                                                                             53 ± 6                                          Before treatment  628 ± 92*                                                                           38 ± 4                                          After treatment  400 ± 53                                                                              69 ± 6**                                       Duodenum:                                                                     Control          39 ± 6 41 ± 5                                          Before treatment 48 ± 3 35 ± 4                                          After treatment  48 ± 3 39 ± 7                                          ______________________________________                                         *Probability < 0.05 relative to the control;                                  **Probability < 0.05 relative to the characteristics before the treatment                                                                              

Therefore, against the background of the treatment with the preparationaccording to the present invention there occurs a reduction of anincreased number of G-cells producing gastrin which is combined with anincrease of the reduced number of D-cells producing somatostatin.

Clinical tests of the preparation according to the present inventionhave shown its high effectiveness in respect of healing of duodenalulcer which is superior over that of cymethidin. The preparationaccording to the present invention contributes to a rapid disappearanceof the pain syndrome lowers the basal secretion of hydrochloric acid,intensifies regeneration processes in the gastroduodenal mucous membrane(according to the data of the mitotic index determination). Thepreparation according to the present invention is nontoxic, does notaffect functions of the most important visceral organs, causes nochanges in the blood characteristics, does not affect endocrinic glands.

The preparation according to the present invention can be used invarious pharmaceutical forms, namely in the form of injectionablesolutions, tablets, suppositoria. It is also possible to use theintranasal mode of its administration. When administered in the form ofinjectionable solutions, the latter contain 0.1-0.5% by weight of theactive ingredient. The injectable solution is administered in the doseof 1 ml 2-3 times a day.

As the solvent use is made of bidistilled water, a 0.9% aqueous solutionof sodium chloride, Ringer's solution, a solution of glucose.

The pharmaceutical preparation according to the present invention in theform of tablets and suppositoria preferably contains the activeprinciple in an amount of 10 to 50 mg per tablet or suppositorium. Forsuppositoria any pharmaceutically acceptable vehicle can be used, fortablets as the pharmaceutical vehicle it is preferred to use starch,glucose, lactose.

The preparation is administered in a dose of 1-2 tablets 3 times a daybefore meals. The course of treatment with the preparation according tothe present invention takes 14 to 28 days. The preparation according tothe present invention has no side effects or contrainidications to itsadministration. Ready pharmaceutical forms of the preparation accordingto the present invention are produced by conventional processes. Theactive principle of the preparation of this invention can be synthesizedby standard procedures of the peptide chemistry, for example by themethod of a step-wise propagation of a peptide chain, starting from theC-terminal free arginine, by means of activated esters of substitutedaminoacids through the following intermediate compounds:carbobenzoxy-leucyl-arginine; carbodenzoxy-phenylalanyl-leucyl-arginine;carbobenzoxy-glycyl-phenylalanyl-arginine;carbodenzoxy-D-alanyl-glycol-phenylalanyl-leucyl-arginine;carbobenzoxy-O-benzyl-tyrozyl-D-alanyl-glycyl-phenylalanyl-leucyl-arginine

INDUSTRIAL APPLICABILITY

The preparation according to the present invention is useful in thegastroenterology as a pharmaceutical preparation for the treatment ofthe peptic ulcer disease.

We claim:
 1. A process for the treatment of peptic ulcer in a warmblooded animal which comprises administering to said warm blooded animalan anti-peptic ulcer effective amount of a peptide of the followingstructure:

    Tyr-D-Ala-Gly-Phe-Leu-Arg

in a pharmaceutically acceptable carrier.
 2. A process for the treatmentof peptic ulcers in a warm blooded animal which comprises administeringto said warm blooded animal a pharmaceutically acceptable amount of thepreparation of claim 1, an injectable solution containing as the activeingredient said peptide in an amount of from 0.1 to 0.5% by weight.
 3. Aprocess for the treatment of peptic ulcers in a warm blooded animalwhich comprises administering to said warm blooded animal apharmaceutically acceptable amount of the preparation of claim 1,wherein said carrier is bidistilled water.
 4. A process for thetreatment of peptic ulcers in a warm blooded animal which compriseadministering to said warm blooded animal a pharmaceutically acceptableamount of the preparation of claim 1, wherein said carrier is a 0.90%aqueous solution of sodium-chloride.
 5. A process for the treatment ofpeptic ulcers in a warm blooded animal which comprises administering tosaid warm blooded animal a pharmaceutically acceptable amount of thepreparation of claim 1, wherein said preparation is in the form oftablets and contains as the active ingredient said peptide in an amountof 10 to 50 mg per tablet.
 6. A process for the treatment of pepticulcers in a warm blooded animal which comprises administering to saidwarm blooded animal a pharmaceutically acceptable amount of thepreparation of claim 1, wherein said preparation contains as apharmaceutically acceptable carrier, a filler selected from the groupconsisting of starch, glucose or lactose.